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Schizophrenia - Dopamine hypothesis
The dopamine hypothesis of schizophrenia or the dopamine hypothesis of psychosis is a theory that argues that the unusual behaviour and experiences associated with schizophrenia (sometimes extended to psychosis in general) can be fully or largely explained by changes in dopamine function in the brain. Some researchers have suggested that overactivity of dopamine systems in the mesolimbic pathway may contribute to the 'positive symptoms' of schizophrenia (such as delusions and hallucinations), whereas problems with dopamine function in the mesocortical pathway may be responsible for the 'negative symptoms', such as avolition, flat emotional response and alogia. This theory is now thought to be too simple to be a complete explanation for the development of psychosis and schizophrenia, although it has been instrumental in motivating experiments which have highlighted the role of dopamine in psychotic states. Methodologies for testing the dopamine hypothesis The hypothesis has been tested using a number of strategies: Drug effects as analogues of schizophrenia Amphetamine models Some of the most obvious evidence for the theory is from the effect of drugs such as amphetamine and cocaine. These drugs (and others like them) increase levels of dopamine in the brain and can cause psychosis, particularly after large doses or prolonged use. This is often referred to as 'amphetamine psychosis' or 'cocaine psychosis', but may produce experiences virtually indistinguishable from the positive symptoms associated with schizophrenia. More recent experimental studies have shown that amphetamine increases the level and intensity of psychotic symptoms in people who already have, or are liable to psychosis. Some functional neuroimaging studies have also shown that, after taking amphetamine, patients diagnosed with schizophrenia show greater levels of dopamine release (particularly in the striatum) than non-psychotic individuals. Action of antipsychotics Another important development was an accidental discovery that a group of drugs called the phenothiazines, including antipsychotics such as chlorpromazine, antagonized dopamine binding (particularly at receptors known as D2 dopamine receptors) and reduced positive psychotic symptoms. This link was strengthened by experiments in the 1980s which suggested that the affinity of antipsychotic drugs for the D2 dopamine receptor family seemed to be correlated with the reduction of psychotic symptoms. However experiments, conducted as new methods were developed (particularly the ability to use PET scanning to examine drug action in the brain of living patients) challenged the view that the amount of dopamine blocking was correlated with clinical benefit. These studies showed that some patients had over 90% of their D2 receptors blocked by antipsychotic drugs, but showed little reduction in their psychoses, suggesting that dopamine overactivity was not a complete explanation. Similarly, a new generation of antipsychotic drugs (called the atypical antipsychotics) were found to be just as effective as older typical antipsychotic drugs in controlling psychosis, but actually blocked fewer dopamine receptors. With the exception of amisulpride, the newer antipsychotic drugs have an additional effect on serotonin function, suggesting that other neurotransmitters are important. Support from genetic studies Genetic evidence has suggested that there may be genes, or specific variants of genes, that code for mechanisms involved in dopamine function, which may be more prevalent in people experiencing psychosis or diagnosed with schizophrenia. Dopamine related genes linked to psychosis in this way included COMT and DRD4. Postmortem investigations While a limited number of studies have shown altered level of dopamine and homovanillic acid, one of its metabolites, in postmortem brains other results have proved negative or inconclusive. For example Haracz (1982) in a review covering studies of the caudate, frontal lobe, cingulate gyrus, nucleus accumbus, putamen and the septal region, noted the lack of association. Of 14 studies of the nucleus accumbens only one reported raised dopamine levels. Monoamine oxidase Monoamine oxidase is an enzyme that degrades dopamine and some had hypothesised that this could be a mediating factor (Wyatt et al 1979). Studies of Dopamine metabolites in body fluids Cerebrospinal fluid Blood Urine Conclusion Psychiatrist David Healy has argued that drug companies have inappropriately promoted the dopamine hypothesis of schizophrenia as it makes for an easy explanation for doctors to understand and communicate to their patients, and implies that drugs which affect dopamine (i.e. antipsychotics) are a 'cure'. Healy argues that this is deliberate simplification of a complex disorder for the benefit of drug marketing. See also * Amphetamine psychosis * Antipsychotic * Dopamine * Psychosis * Schizophrenia Further reading * Healy, D (2002) The Creation of Psychopharmacology. ISBN 0674006194 * Jones, H. M., & Pilowsky, L. S. (2002) Dopamine and antipsychotic drug action revisited. British Journal of Psychiatry, 181, 271-275. Full text Dopamine hypothesis of psychosis Category:Schizophrenia Category:Schizophrenia - Neurochemistry